It is now appreciated that many mammalian species encode factors conferring resistance to retroviral infections. Some, such as the APOBEC3 family of cytidine deaminases, modify minus strand viral DNA during reverse transcription, resulting in either its degradation or its integration into host chromosomal DNA as a hypermutated provirus. The deleterious activities of APOBEC3G are countered by lentiviral Vif proteins, which prevent the encapsidation of APOBEC3G into nascent virions. The sensitivity of APOBEC3G from different animal species to the Vif proteins expressed by different viruses varies widely. For example, while HIV-1 Vif can potently suppress human APOBEC3G, it is not effective against rhesus monkey APOBEC3G, explaining in part, the restriction of HIV-1 replication in macaque cells. Another recently described restriction factor, TRIM5 alpha, targets incoming viral capsids and blocks retroviral replication in a species specific manner. For example, TRIM5 alpha from rhesus macaques potently suppresses HIV-1 but not SIV infectivity in monkey cells. Although its mechanism of action is still unclear, TRIM5 alpha restriction is thought to affect virus uncoating, thereby blocking subsequent steps in the replication cycle. [unreadable] [unreadable] HIV-1 derivatives have been constructed, which carry only the SIVmac239 vif gene and a short seven amino acid segment from SIV gag corresponding to the HIV-1 CypA-binding loop. Molecularly cloned viruses bearing these two SIV regions are able to establish spreading infections in a cynomolgus monkey (CyM) T cell line and CD8 depleted PBMCs from pig-tailed macaques (PtM) and rhesus monkeys (RhM). These results indicate that the incorporation of two SIV gene segments into the HIV-1 genome can effectively counter two known species specific restriction factors that block virus replication in monkey cells. They raise the possibility of generating HIV-1 derivatives, containing all of its structural proteins, and capable of infecting macaque monkeys.